Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
Authors: Paul Bastard, Sara E. Vazquez, Jamin Liu, Matthew T. Laurie, Chung Yu Wang, Adrian Gervais, Tom Le Voyer, Lucy Bizien, Colin Zamecnik, Quentin Philippot, Jérémie Rosain, Emilie Catherinot, Andrew Willmore, Anthea M. Mitchell, Rebecca Bair, Pierre Garçon, Heather Kenney, Arnaud Fekkar, Maria Salagianni, Garyphallia Poulakou, Eleni Siouti, Sabina Sahanic, Ivan Tancevski, Günter Weiss, Laurenz Nagl, Jérémy Manry, Sotirija Duvlis, Daniel Arroyo-Sánchez, Estela Paz Artal, Luis Rubio, Cristiano Perani, Michela Bezzi, Alessandra Sottini, Virginia Quaresima, Lucie Roussel, Donald C. Vinh, Luis Felipe Reyes, Margaux Garzaro, Nevin Hatipoglu, David Boutboul, Yacine Tandjaoui-Lambiotte, Alessandro Borghesi, Anna Aliberti, Irene Cassaniti, Fabienne Venet, Guillaume Monneret, Rabih Halwani, Narjes Saheb Sharif-Askari, Jeffrey Danielson, Sonia Burrel, Caroline Morbieu, Yurii Stepanovskyy, Anastasia Bondarenko, Alla Volokha, Oksana Boyarchuk, Alenka Gagro, Mathilde Neuville, Bénédicte Neven, Sevgi Keles, Romain Hernu, Antonin Bal, Antonio Novelli, Giuseppe Novelli, Kahina Saker, Oana Ailioaie, Arnau Antolí, Eric Jeziorski, Gemma Rocamora-Blanch, Carla Teixeira, Clarisse Delaunay, Marine Lhuillier, Paul Le Turnier, Yu Zhang, Matthieu Mahevas, Qiang Pan-Hammarström, Hassan Abolhassani, Thierry Bompoil, Karim Dorgham, Guy Gorochov, Cédric Laouenan, Carlos Rodríguez-Gallego, Lisa F. P. Ng, Laurent Renia, Aurora Pujol, Alexandre Belot, François Raffi, Luis M. Allende, Javier Martinez-Picado, Tayfun Ozcelik, Luisa Imberti, Luigi D. Notarangelo, Jesus Troya, Xavier Solanich, Shen-Ying Zhang, Anne Puel, Michael R. Wilson, Sophie Trouillet-Assant, Laurent Abel, Emmanuelle Jouanguy, Chun Jimmie Ye, Aurélie Cobat, Leslie M. Thompson, Evangelos Andreakos, Qian Zhang, Mark S. Anderson, Jean-Laurent Casanova, Joseph L. DeRisi
Journal: Science Immunology (2022)

Life-threatening “breakthrough” cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.